Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for grouping of substances and read-across

The Short Chain Alcohol Esters (SCAE C2-C8) category covers esters from a fatty acid (C8-C29) and a C2-C8 alcohol (ethanol, isopropanol, butanol, isobutanol, pentanol, iso-pentanol, hexanol, 2-ethylhexanol or octanol). This category includes both well-defined mono-constituent substances as well as related UVCB substances with varying fatty acid chain lengths.

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate, environmental and human health hazards. Thus where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

Overview of reproductive toxicity

CAS #

Toxicity

111-62-6 (a)

NOAEL: 5500 mg/kg bw/day

123-95-5 (a)

NOAEL: 6000 mg/kg bw/day

(a) Category members subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font.

CAS 111-62-6

NOAEL (fertility) = 5500 mg/kg bw/day, OECD 408

A 90-day oral feeding study (Bookstaff, 2004) was performed with Ethyl Oleate (CAS# 111-62-6) according to the 1993 FDA draft "Redbook II" guidelines (Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food). The study was performed equivalently to OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents) with additional assessment of oestrus cycle and sperm parameters. The purpose of the study was to determine the safety of Ethyl Oleate (EO) in a 91-day feeding study in Sprague-Dawley rats. EO was mixed into AIN-93G purified diet at levels of approx. 0, 1900, 3800 and 6000 mg/kg bw/day. All diets were calorie- and fat-matched using high oleic safflower oil (HOSO) as the control fat. There were 20 male and 20 female rats per group. EO in the diet was well tolerated and there were no toxicologically significant findings in any of the measured parameters (clinical observations, body weight gains, appearance of the faeces, ophthalmic examinations, haematology, clinical chemistry, urinalysis, organ weights, histopathology, or male and female reproductive assessments). Based on the absence of abnormalities concerning oestrus cyclus, sperm characterization and histopathologic evaluation of oestrus cycle in females, sperm characterization in males and histologic examinations (incl. epididymides, mammary gland, ovaries, prostate, seminal vesicles, testes, thyroid with parathyroid, uterus with uterine horns and Vagina) the subchronic 90-day oral NOAEL for fertility in rats for Ethyl Oleate was found to be approx. 5500 mg/kg bw/d.

 

CAS 123-95-5 

NOAEL (parental fertility) = 6000 mg/kg bw/day, OECD 421

NOAEL (offspring development) = 6000 mg/kg bw/day, OECD 421

A reproduction/developmental toxicity screening test was performed with Butyl Stearate (CAS# 123-95-5) similar to OECD Guideline 421 (Smith, 1953). 20 male and female Sprague-Dawley rats received Butyl Stearate at a concentration of 6.25% in the diet, corresponding to approx. 6000 mg/kg bw/day for a period of 10 weeks. Negative control animals (12 males and females) were fed with the concurrent basal diet. After 10 weeks animals were mated. Successfully mated pregnant females were housed individually in breeding cages. The date of parturition and the number and sex of pups in each litter were recorded. Litters were weaned 21 days postpartum and the weights of the weanlings determined. From each of the three groups of weanlings (those receiving the test material and the controls), 24 males and 24 females were chosen at random and for the next 21 days, these young were fed the same 6.25% diet as had been ingested by their parents. Diet intake and body weights were recorded daily; 21 days after weaning, the rats were sacrificed and necropsies were performed.

Based on reproduction, fertility index, litter size, survival index/viability index of offspring and necropsy at day 21 after weaning the NOAEL for parental fertility as well as for offspring development was found to be 6000 mg/kg bw/d.

 

Conclusion for reproduction toxicity

Two studies investigating the reproduction toxicity are available within theShort Chain Alcohol Esters (SCAE C2-C8). The studies from the category members Ethyl Oleate (CAS# 111-62-6) and Butyl Stearate (CAS# 123-95-5) did not show treatment-related effects up to the highest tested dose level. Thus, no hazard for reproduction toxicity was identified.

A waiver for the requirement to perform an extended one-generation reproduction toxicity study (standard configuration or with additional modules) was included, as the study is not scientifically necessary and, considering concerns regarding the use of vertebrate animals for experimental purposes, unjustified.

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.

Short description of key information:

Studies on reproduction toxicity/fertility were available for the following category members (CAS#): 111-62-6 and 123-95-5.

For ethyl oleate and butyl stearate a 90-day subchronic NOAEL for fertility was found to be 5500 and 6000 mg/kg bw/d in rats.

Effects on developmental toxicity

Description of key information

The NOAEL for maternal and developmental toxicity for 2-ethylhexylstearate (CAS# 91031-48-0) and for 2-ethyl hexyl stearate (CAS# 22047-49-0) was found to be 1000 mg/kg bw/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for grouping of substances and read-across

The Short Chain Alcohol Esters (SCAE C2-C8) category covers esters from a fatty acid (C8-C29) and a C2-C8 alcohol (ethanol, isopropanol, butanol, isobutanol, pentanol, iso-pentanol, hexanol, 2-ethylhexanol or octanol). This category includes both well-defined mono-constituent substances as well as related UVCB substances with varying fatty acid chain lengths.

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate, environmental and human health hazards. Thus where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

 

Overview of developmental toxicity

CAS #

Toxicity

22047-49-0 (a)

NOAEL: 1000 mg/kg bw/day

91031-48-0 (a)

NOAEL: 1000 mg/kg bw/day

(a) Category members subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font.

 

CAS 22047-49-0

NOAEL (maternal toxicity) = 1000 mg/kg bw/day, OECD 414

NOAEL (embryo-/fetotoxicity and teratogenicity) = 1000 mg/kg bw/day, OECD 414

The developmental toxicity of 2-Ethylhexyl Stearate (CAS 22047-49-0) was investigated according to OECD Guideline 414 and GLP conditions (Aulmann, 2000). Groups of 24 female Sprague-Dawley rats received daily oral gavage doses of the test substance in arachidis oil at dose levels of 0, 100, 300 and 1000 mg/kg bw/d during gestational days 6 to 15. On day 20 of gestation the animals were euthanized and examined for maternal and fetal parameters. Based on the number of implantations, number of total litter losses by resorption, mortality, clinical signs, body weight, gross pathology and organ weights of maternal animals the NOAEL for maternal toxicity was found to be 1000 mg/kg bw/d. Examination of fetus litter size and weights, offspring viability (number alive and number dead), sex ratio, grossly visible abnormalities, external, head, soft tissue and skeletal abnormalities showed no differences to control and no indication for teratogenic effects. Therefore, the NOAEL for embryo-/fetotoxicity and teratogenicity in rats for 2-Ethylhexyl Stearate was found to be 1000 mg/kg bw/day.

 

 

CAS 91031-48-0

NOAEL (maternal toxicity) = 1000 mg/kg bw/day, OECD 414

NOAEL (embryo-/fetotoxicity and teratogenicity) = 1000 mg/kg bw/day, OECD 414

A Prenatal Developmental Toxicity Study was performed with Fatty Acids, C16-18, 2-Ethylhexyl Esters (CAS 91031-48-0) according to OECD Guideline 414 (Pittermann, 1994). Groups of 24 female Sprague-Dawley rats received daily oral gavage doses of the test substance in arachidis oil at dose levels of 0, 100, 300 and 1000 mg/kg bw/day during gestational days 6 to 15. On day 20 of gestation the animals were euthanized and examined for maternal and fetal parameters. Based on the number of implantations, number of total litter losses by resorption, mortality, clinical signs, body weight, gross pathology and organ weights of maternal animals the NOAEL for maternal toxicity was found to be 1000 mg/kg bw/day. Examination of fetus litter size and weights, offspring viability (number alive and number dead), sex ratio, grossly visible abnormalities, external, head, soft tissue and skeletal abnormalities showed no differences to control and no indication for teratogenic effects. Therefore, the NOAEL for embryo-/foetotoxicity and teratogenicity in rats for Fatty Acids C16-18, 2-Ethylhexyl Esters was found to be 1000 mg/kg bw/day.

 

 

Conclusion for developmental toxicity

Two studies investigating the developmental toxicity are available within theShort Chain Alcohol Esters (SCAE C2-C8). The studies from the category members2-Ethylhexyl Stearate (CAS 22047-49-0) and Fatty Acids, C16-18, 2-Ethylhexyl Esters (CAS 91031-48-0)did not show treatment-related effects up to the highest tested dose level. Thus, no hazard for developmental toxicity was identified.

A waiver for the requirement to perform a prenatal developmental toxicity study in a 2nd species was included, as this requirement is considered not to add new information for hazard assessment and therefore is scientifically and, considering concerns regarding the use of vertebrate animals for experimental purposes, unjustified.

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met.

Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint".

Since the group concept is applied to the members of the SCAE C2 -8 category, data will be generated from representative reference substance(s) within the category to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labeled on this basis.

Therefore, based on the group concept, the available data on toxicity to reproduction and development do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.